This invention relates to compounds for inhibiting bone resorption that is mediated by the action of a class of cells known as osteoclasts.
Osteoclasts are multinucleated cells of up to 400 .mu.m in diameter that resorb mineralized tissue, chiefly calcium carbonate and calcium phosphate, in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acids and proteases and thereby cause the actual resorption of mineralized tissue from the bone.
The pharmacologic activity of these compounds is useful in the treatment of mammals, including man.
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, and glucocorticoid treatment.
All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation, which continues throughout life at the rate of about 14% per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
Endothelial cells secrete growth factors that are mitogenic for endothelium and can induce formation of new blood vessels (angiogenesis). Angiogenic stimuli cause the elongation or proliferation of endothelial cells and generation of new vessels.